CN120983442A - Application of MLN4924 and flubendazole in the preparation of drugs for treating atherosclerosis - Google Patents
Application of MLN4924 and flubendazole in the preparation of drugs for treating atherosclerosisInfo
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- CN120983442A CN120983442A CN202511509783.0A CN202511509783A CN120983442A CN 120983442 A CN120983442 A CN 120983442A CN 202511509783 A CN202511509783 A CN 202511509783A CN 120983442 A CN120983442 A CN 120983442A
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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Abstract
The invention discloses application of MLN4924 and flubendazole in preparing medicaments for treating atherosclerosis. The low-dose MLN4924 and the flubendazole have almost no cytotoxicity, can treat atherosclerosis by interfering foam cell formation and cholesterol accumulation, and have stronger effect by combined use, thereby realizing synergistic effect.
Description
Technical Field
The invention belongs to the technical field of atherosclerosis, and particularly relates to application of MLN4924 and flubendazole in preparing medicines for treating atherosclerosis.
Background
Atherosclerosis is a chronic progressive disease characterized by high morbidity and mortality worldwide, and is the leading pathological basis for cardiovascular and cerebrovascular diseases. According to world health organization data, cardiovascular disease is the leading cause of death worldwide throughout the year, with the vast majority being caused by atherosclerosis. Along with life style changes caused by population aging and urban process, the disease burden is increasingly heavy, and the prevalence of main risk factors of atherosclerosis such as hypertension, dyslipidemia and the like is continuously increased.
At present, the drug treatment of atherosclerosis forms a comprehensive management strategy by taking statin lipid-lowering drugs as basic stones and combining anti-platelet drugs, antihypertensive drugs and hypoglycemic drugs. The core goal of these drugs is to control risk factors, stabilize plaque to prevent rupture or erosion, thereby significantly reducing the risk of major adverse cardiovascular events such as myocardial infarction and stroke. However, side effects of long-term administration, such as statin-related myalgia, liver enzyme abnormalities, and bleeding risk with antiplatelet drugs, seriously affect patient compliance.
Disclosure of Invention
The invention aims to provide application of MLN4924 and flubendazole in preparing medicines for treating atherosclerosis.
Use of MLN4924 and flubendazole for the preparation of a medicament for the treatment of atherosclerosis.
MLN4924 and flubendazole inhibit foam cell formation.
MLN4924 and flubendazole inhibit cholesterol accumulation.
A medicine for treating atherosclerosis comprises MLN4924 and flubendazole as active ingredients.
Preferably, the dosage mass ratio of the MLN4924 to the flubendazole is 1:4.
Preferably, one or more pharmaceutically acceptable excipients or carriers are also included.
Preferably, the auxiliary materials or carriers comprise diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers or lubricants.
Preferably, the pharmaceutical composition can be prepared into dosage forms of tablets, capsules, effervescent tablets, granules, powder, dispersible tablets, oral liquid, pills or injection.
The invention has the beneficial effects that the low-dose MLN4924 and the flubendazole have almost no cytotoxicity, can be used for treating atherosclerosis by intervening foam cell formation and cholesterol accumulation, and have stronger effect and realize synergy.
Drawings
FIG. 1 shows the cellular activity of varying concentrations of MLN4924 on THP-1 derived macrophages.
FIG. 2 shows the measurement results of the oil red dyeing area of example 2.
FIG. 3 shows the cellular activity of varying concentrations of flubendazole on THP-1-derived macrophages.
FIG. 4 shows the measurement results of the oil red dyeing area of example 4.
FIG. 5 shows the measurement results of the oil red dyeing area of example 5.
FIG. 6 shows the results of measuring the intracellular cholesterol content of example 6.
FIG. 7 shows the results of the atherosclerosis inhibition assay in the mouse model of example 7, wherein A is the plaque area calculated by oil red O staining of the aorta of the mice, and B is the plaque absolute area calculated by HE staining of the aortic root plaque sections of the mice.
Detailed Description
The present invention will be described more fully hereinafter in order to facilitate an understanding of the present invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
MLN4924 used in the examples below was purchased from MedChemexpress under the trade designation HY-70062 and flubendazole was purchased from MCE under the trade designation HY-B0294.
EXAMPLE 1 Low concentration of MLN4924 no significant cytotoxicity on THP-1 derived macrophages
Human monocyte THP-1 is selected as a study object, a culture medium is prepared according to the proportion of 90% RPMI1640 culture medium (PYG 0006, wuhan Boschia Biotech Co., ltd.)) +10% serum (FSP 500, eichhornia Biotech Co., ltd.)) +1% double antibody (2240831, thermo Fisher Co., USA) is cultured in an environment with 37 ℃ and 5% carbon dioxide concentration, when the cell state is good, an inducer PMA (Phorbol-myristate 13-acetate) is added to induce for 24 hours to divide into macrophages, then MLN4924 with different concentrations is added, and after 48 hours of action, CCK-8 cell proliferation and toxicity detection are carried out.
The experimental method comprises the following steps:
(1) THP-1 cells were plated in 96-well plates and induced by addition of PMA (20 ng/ml) for 24 hours;
(2) Different concentrations of MLN4924 (0, 0.25. Mu.M, 0.5. Mu.M, 0.75. Mu.M, 1. Mu.M) were added for 24 hours;
(3) Adding 0.5mlCCK-8 reagent into 9.5ml culture medium, and mixing;
(4) The medium in the 96-well plate was aspirated, 100ml of CCK-8 reagent working solution was added to each well, and after 2 hours in the incubator, the absorbance at 450nm was measured using an M5 microplate reader.
The statistical analysis uses a single-factor analysis of variance, and the experimental results are shown in FIG. 1, which show that the low-dose MLN4924 (less than or equal to 1 mu M) has no obvious cytotoxicity to the macrophages from THP-1 sources.
EXAMPLE 2 MLN4924 inhibits foam cell formation
PMA was added to THP-1 cells to induce differentiation into macrophages, MLN4924 (1. Mu.M) was added to the experimental group after 24 hours, oxLDL was added to the experimental group and the control group after 24 hours, and oil red staining was performed after 24 hours.
The experimental method comprises the following steps:
(1) THP-1 cells were plated in 12-well plates with cell climbing plates and induced by PMA (20 ng/ml) for 24 hours;
(2) After 24 hours of treatment with MLN4924 (1. Mu.M), oxLDL (20. Mu.g/ml) was added and incubated for 24 hours;
(3) Absorbing and discarding the culture medium, and washing once with PBS;
(4) Fixing 10% neutral formaldehyde for 10 min;
(5) Slightly washing with 60% isopropanol (diluted with PBS);
(6) Diluting and standing 0.5% of oil red O solution and water in a ratio of 3:2 for 10 minutes, and filtering with medium-speed qualitative filter paper;
(7) Dyeing for 30 minutes, adding 60% isopropanol and slightly washing;
(8) Hematoxylin nuclear dyeing and tap water washing;
(9) Taking out the climbing sheet, sealing the climbing sheet with glycerin gelatin, and taking a picture under a microscope;
(10) Quantitative statistics of oil red staining area were performed using Image J software.
The statistical analysis uses a one-way analysis of variance, and the experimental results are shown in FIG. 2. After MLN4924 is added before oxLDL action, the oil red staining area of macrophages is obviously reduced compared with the control group. The above results suggest that MLN4924 inhibits foam cell formation.
Example 3 Low concentration of flubendazole no significant cytotoxicity to THP-1 derived macrophages
Human monocyte THP-1 is selected as a research object, the culture medium is prepared by mixing 90% RPMI1640 culture medium with 10% serum with 1% double antibody, culturing in an environment with 37 ℃ and 5% carbon dioxide concentration, adding an inducer PMA to induce 24 hours to differentiate into macrophages when the cell state is good, adding flubendazole with different concentrations, and performing CCK-8 cell proliferation and toxicity detection after 48 hours of action.
The experimental method comprises the following steps:
(1) THP-1 cells were plated in 96-well plates and induced by addition of PMA (20 ng/ml) for 24 hours;
(2) Treatment was performed by adding flubendazole (0, 0.25. Mu.M, 0.5. Mu.M, 0.75. Mu.M, 1. Mu.M) at various concentrations for 24 hours;
(3) Adding 0.5mlCCK-8 reagent into 9.5ml culture medium, and mixing;
(4) The medium in the 96-well plate was aspirated, 100ml of CCK-8 reagent working solution was added to each well, and after 2 hours in the incubator, the absorbance at 450nm was measured using an M5 microplate reader.
The statistical analysis uses single factor analysis of variance, the experimental results are shown in figure 3, and the results show that the low-dose flubendazole (less than or equal to 1 mu M) has no obvious cytotoxicity on the macrophages from THP-1 sources.
Example 4 inhibition of foam cell formation by flubendazole
PMA was added to THP-1 cells to induce differentiation into macrophages, flubendazole (1. Mu.M) was added to the experimental group after 24 hours, oxLDL was added to the experimental group and the control group after 24 hours, and oil red staining was performed after 24 hours.
The experimental method comprises the following steps:
(1) THP-1 cells were plated in 12-well plates with cell climbing plates and induced by PMA (20 ng/ml) for 24 hours;
(2) After 24 hours of treatment with flubendazole (1. Mu.M), oxLDL (20. Mu.g/ml) was added and incubated for 24 hours;
(3) Absorbing and discarding the culture medium, and washing once with PBS;
(4) Fixing 10% neutral formaldehyde for 10 min;
(5) Slightly washing with 60% isopropanol (diluted with PBS);
(6) Diluting and standing 0.5% of oil red O solution and water in a ratio of 3:2 for 10 minutes, and filtering with medium-speed qualitative filter paper;
(7) Dyeing for 30 minutes, adding 60% isopropanol and slightly washing;
(8) Hematoxylin nuclear dyeing and tap water washing;
(9) Taking out the climbing sheet, sealing the climbing sheet with glycerin gelatin, and taking a picture under a microscope;
(10) Quantitative statistics of oil red staining area were performed using Image J software.
The statistical analysis uses single factor analysis of variance, the experimental results are shown in figure 4, and after the flubendazole is added before the oxLDL acts, the oil red staining area of the macrophage is obviously reduced compared with the control group, and the results indicate that the flubendazole inhibits the formation of foam cells.
Example 5 MLN4924 and Fluobendazole 1:4 mixtures were effective in inhibiting foam cell formation
PMA was added to THP-1 cells to induce differentiation into macrophages, MLN4924 (1. Mu.M), flubendazole (1. Mu.M), and a 1:4 mixture of MLN4924 and flubendazole (0.2. Mu.M MLN4924 plus 0.8. Mu.M flubendazole) were added after 24 hours, and oxLDL was added to induce formation of foam cells in each group after 24 hours, followed by oil red staining.
The experimental method comprises the following steps:
(1) THP-1 cells were plated in 12-well plates with cell climbing plates and induced by PMA (20 ng/ml) for 24 hours;
(2) MLN4924 (1. Mu.M), flubendazole (1. Mu.M), and a 1:4 mixture of MLN4924 and flubendazole (0.2. Mu.M MLN4924 plus 0.8. Mu.M flubendazole) were added, respectively, and after 24 hours, oxLDL (20. Mu.g/ml) was added and incubated for 24 hours;
(3) Absorbing and discarding the culture medium, and washing once with PBS;
(4) Fixing 10% neutral formaldehyde for 10 min;
(5) Slightly washing with 60% isopropanol (diluted with PBS);
(6) Diluting and standing 0.5% of oil red O solution and water in a ratio of 3:2 for 10 minutes, and filtering with medium-speed qualitative filter paper;
(7) Dyeing for 30 minutes, adding 60% isopropanol and slightly washing;
(8) Hematoxylin nuclear dyeing and tap water washing;
(9) Taking out the climbing sheet, sealing the climbing sheet with glycerin gelatin, and taking a picture under a microscope;
(10) Quantitative statistics of oil red staining area were performed using Image J software.
The statistical analysis uses single factor analysis of variance, the experimental results are shown in figure 5, and after the mixture of MLN4924 and flubendazole 1:4 is treated, the oil red staining area of the macrophage is obviously reduced compared with that of the control group and the independent action groups of MLN4924 and flubendazole. The results of the experiment are shown in FIG. 5, and the results suggest that the mixture of MLN4924 and flubendazole 1:4 can synergistically inhibit the formation of foam cells.
Example 6 MLN4924 and Fluobendazole 1:4 mixtures are effective in inhibiting cholesterol accumulation
PMA was added to THP-1 cells to induce differentiation into macrophages, MLN4924 (1. Mu.M), flubendazole (1. Mu.M), and a 1:4 mixture of MLN4924 and flubendazole (0.2. Mu.M MLN4924 plus 0.8. Mu.M flubendazole) were added after 24 hours, and oxLDL was added to each group to induce formation of foam cells after 24 hours, and the intracellular cholesterol content was measured.
The experimental method comprises the following steps:
(1) THP-1 cells were plated in 6-well plates and induced by addition of PMA (20 ng/ml) for 24 hours;
(2) MLN4924 (1. Mu.M), flubendazole (1. Mu.M), and a 1:4 mixture of MLN4924 and flubendazole (0.2. Mu.M MLN4924 plus 0.8. Mu.M flubendazole) were added, respectively, and after 24 hours, oxLDL (20. Mu.g/ml) was added and incubated for 24 hours;
(3) The medium was aspirated and 0.5ml PBS was added to each well to scrape off the cells and collect them into the EP tube, and the cells were centrifuged at 1000 rpm for 10 minutes, the supernatant was discarded, and the procedure was repeated and washed 2 more times with PBS;
(4) Adding the cell sediment into the lysate, performing ultrasonic disruption (power 300W,3 seconds/time, 15 seconds and 3 minutes intervals) under the ice water bath condition, and directly measuring the lysed liquid without centrifugation;
(5) Total cholesterol test, wherein the measurement system is 2.5 mu l of lysate (blank hole is added with 2.5 mu l of distilled water, calibration hole is added with 2.5 mu l of calibrator, sample hole is added with 2.5 mu l of lysate) and 250 mu l of working solution (Nanjing built total cholesterol test box, product number A111-1-1) are added, 3 repeated holes are arranged in each group, the mixture is uniformly mixed, incubation is carried out for 10 minutes at 37 ℃, and the absorbance value of each hole is measured by an enzyme-labeling instrument at the wavelength of 510 nm.
The statistical analysis uses single factor analysis of variance, the experimental result is shown in figure 6, after the mixture of MLN4924 and flubendazole 1:4 is treated, the content of cholesterol in cells is obviously reduced compared with the control group and the independent action groups of MLN4924 and flubendazole, and the mixture of MLN4924 and flubendazole 1:4 can synergistically inhibit the accumulation of cholesterol.
EXAMPLE 7 MLN4924 and Fluobendazole 1:4 mixture inhibiting the atherosclerotic Process in a mouse model
To further investigate the function of MLN4924 and fluorobenzdazole in the course of atherosclerosis, we selected the currently accepted mouse model ApoE-/-mouse for the study of atherosclerosis. We randomly divided eight week old ApoE-/-mice into four groups, three experimental groups were injected with 5mg/kg MLN4924, 5mg/kg fluorobbendazole, a mixture of MLN4924 and fluorobbendazole 1:4 (1 mg/kg MLN4924 plus 4mg/kg fluorobbendazole), control groups were injected with 200. Mu.L/kg PBS (twice a week for 12 weeks), and high fat feeding was performed to establish an atherosclerosis model.
The experimental method comprises the following steps:
(1) The mice are anesthetized and sacrificed after being induced by high-fat diet, and viscera are removed;
(2) Removing the whole aorta and removing adipose tissue around the aorta;
(3) Longitudinally shearing the aorta of the mouse, and paving the inner membrane surface downwards;
(4) 0.5 ml of 4% paraformaldehyde was added to fix at 4℃overnight;
(5) 5 ml PBS rinse 2 hours;
(6) PBS rinse after aortic adventitia removal;
(7) Dehydrating in propylene glycol 5 ml at room temperature for 2 min;
(8) 5 ml of 0.5% oil red O for 2 hours at room temperature;
(9) Washing with 85% propylene glycol (PBS dilution) 4 times in sequence;
(10) Washing with PBS;
(11) Scanning and photographing after the aorta is fixed;
(12) The proportion of the plaque area stained with oil red O to the total area of the aorta was calculated, image J software was used for quantitative analysis, and a one-factor analysis of variance was used for statistical analysis to calculate the p-value.
Four groups of mice were phenotyped and a in figure 7 is the plaque area calculated by oil red O staining of the aorta of the mice. The aortic plaque area of the mice in the mixed administration group of MLN4924 and flubendazole 1:4 is obviously lower than that of the mice in the control group and the single administration group of MLN4924 and flubendazole, which shows that the combination of MLN4924 and flubendazole can synergistically inhibit the formation of atherosclerosis plaque.
The experimental method comprises the following steps:
(1) Mice were sacrificed under anesthesia after induction with a high-fat diet, aortic plaque root tissue was isolated and fixed with 10% formalin for 48 hours;
(2) Placing the fixed tissue into an embedding box after repairing the blocks;
(3) Dehydrating the tissue with alcohol gradient for 10min at 70%, 80%, 90%, I, 90%, II, 95%, II, 100%, I and 100% II;
(4) Tissue xylene is transparent, namely xylene I and xylene II are respectively treated for 5 minutes;
(5) Wax dipping the tissues, namely, wax jar I and wax jar II for 40 minutes respectively;
(6) Embedding, namely preparing the tissues into wax blocks;
(7) Slicing with thickness of 4 μm;
(8) The sheet baking machine is used for overnight;
(9) Slicing, dewaxing for 10 min each with xylene I and xylene II, rehydrating for 5min each with 100% I and 100% II alcohol, and 3 min each with 95%, 90%, 80%, 75%;
(10) Washing with water for 2 min for 3 times;
(11) Hematoxylin staining nuclei for 10 minutes;
(12) Washing with tap water for 2 minutes;
(13) Eosin staining for 2 min;
(14) Washing with tap water for 2 minutes;
(15) 90% and 100% alcohol for 2 min each, and xylene I and xylene II for 4 min each;
(16) A neutral resin sealing piece;
(17) Photographs were taken using a Nikon Bx60 microscope with a Nikon DP70 camera attached, quantitative analysis using Image J software, and statistical analysis using one-way analysis of variance to calculate p-values.
In fig. 7B is the absolute plaque area calculated by HE staining of the aortic root plaque sections of the mice. The aortic root plaque area of the mice in the mixed administration group of MLN4924 and flubendazole 1:4 is obviously lower than that of the mice in the control group and the single administration group of MLN4924 and flubendazole, which shows that the combination of MLN4924 and flubendazole can be synergistic and can obviously inhibit atherosclerosis.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (8)
- Use of mln4924 and flubendazole for the preparation of a medicament for the treatment of atherosclerosis.
- 2. The use of MLN4924 and flubendazole for the manufacture of a medicament for the treatment of atherosclerosis according to claim 1, wherein MLN4924 and flubendazole inhibit the formation of foam cells.
- 3. The use of MLN4924 and flubendazole for the manufacture of a medicament for the treatment of atherosclerosis according to claim 1, wherein MLN4924 and flubendazole inhibit the accumulation of cholesterol.
- 4.A medicament for treating atherosclerosis, which is characterized in that the active ingredients are MLN4924 and flubendazole.
- 5. The agent for treating atherosclerosis according to claim 4, wherein the ratio of the amount of MLN4924 to the amount of flubendazole is 1:4 by mass.
- 6. The medicament for the treatment of atherosclerosis according to claim 4 or 5, characterized by further comprising one or more pharmaceutically acceptable excipients or carriers.
- 7. The medicament for treating atherosclerosis according to claim 6, characterized in that said auxiliary materials or carriers comprise diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers or lubricants.
- 8. The medicament for treating atherosclerosis according to claim 4 or 5, wherein the pharmaceutical composition can be prepared into dosage forms of tablets, capsules, effervescent tablets, granules, powders, dispersible tablets, oral liquids, pills or injections.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140135296A1 (en) * | 2011-05-10 | 2014-05-15 | Vojo Deretic | Methods of treating autophagy-associated disorders and related pharmaceutical compositions, diagnostics, screening techniques and kits |
| US20160136123A1 (en) * | 2013-06-14 | 2016-05-19 | Vojo P. Deretic | Treatment of autophagy-related disorders |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140135296A1 (en) * | 2011-05-10 | 2014-05-15 | Vojo Deretic | Methods of treating autophagy-associated disorders and related pharmaceutical compositions, diagnostics, screening techniques and kits |
| US20160136123A1 (en) * | 2013-06-14 | 2016-05-19 | Vojo P. Deretic | Treatment of autophagy-related disorders |
Non-Patent Citations (1)
| Title |
|---|
| XING LEI等: "MLN4924 inhibits macrophage foam cell formation by enhancing autophagy and regulating metabolic phenotyp", LIPIDS IN HEALTH AND DISEASE, vol. 24, 2 October 2025 (2025-10-02), pages 307 * |
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